title: 3D mapping of glycogenosis-causing mutations in the large regulatory alpha subunit of phosphorylase kinase.
abstract: Mutations in the liver isoform of the Phosphorylase Kinase (PhK) alpha subunit (PHKA2 gene) cause X-linked liver glycogenosis (XLG), the most frequent type of PhK deficiency (glycogen-storage disease type IX). XLG patients can be divided in two subgroups, with similar clinical features but different activity of PhK (decreased in liver and blood cells for XLG-I and low in liver but normal or enhanced in blood cells for XLG-II). Here, we show that the PHKA2 missense mutations and small in-frame deletions/insertions are concentrated into two domains of the protein, which were recently described. In the N-terminal glucoamylase domain, mutations (principally leading to XLG-II) are clustered within the predicted glycoside-binding site, suggesting that they may have a direct impact on a possible hydrolytic activity of the PhK alpha subunit, which remains to be demonstrated. In the C-terminal calcineurin B-like domain (domain D), mutations (principally leading to XLG-I) are clustered in a region predicted to interact with the regulatory region of the PhK catalytic subunit and in a region covering this interaction site. Altogether, these results show that PHKA2 missense mutations or small in-frame deletions/insertions may have a direct impact on the PhK alpha functions and provide a framework for further experimental investigation.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, IMPMC-UMR7590, Paris, F-75005, France.
authors.forename: Cathelène
authors.initials: C
authors.lastname: Carrière
authors.forename: Slavica
authors.initials: S
authors.lastname: Jonic
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mornon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
mesh_terms: D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D006008:Glycogen Storage Disease / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010764:Phosphorylase Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D007527:Isoenzymes; D021122:Protein Subunits; D010764:Phosphorylase Kinase